Biomedical Engineering Reference
In-Depth Information
uPAR in the plasma membrane of LOX malignant melanoma cells and FAP-
uPAR complex formation has been demonstrated,
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likely increasing
proteolytic progression of cells through the tumor microenvironment. Such
non-enzymatic roles of FAP are thought to contribute to its roles in pro-
fibrinolysis.
52
In 2005, Wang et al. found that an enzyme negative FAP
mutant over-expressed in the LX-2 human hepatic stellate cell (HSC) resulted
in enhanced cell adhesion, migration and staurosporine streptomyces-stimu-
lated apoptosis, providing further evidence for the importance of FAPs non-
enzymatic roles in the facilitation of tissue remodeling in chronic liver
injury.
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Similar to DP4, FAP expression has also been linked with changes in
MMP expression. Over expression of either FAP or DP4 in 293T cells resulted
in an increase in MMP-2 and CD44 expression accompanied by a reduction in
integrin-b1.
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MMPs are well known for their roles in cell adhesion and
migration via proteolytic degradation of the ECM, and the association of
DP4 and FAP with altered MMP activities most likely contributes to their
observed roles in cancer.
1.4.2 DP8 and DP9: Intracellular Proteins
DP8 was first identified and cloned by Abbott et al. in 2000,
6
almost 40 years
after the initial discovery of DP4. Within the Abbott et al. study, DP9 was first
identified in silico by BLAST alignment with DP8.
6
In 2002, Olsen and
Wagtmann reported the first cloning of the short 863-amino-acid form of
DP9
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followed by repeated cloning of short DP9 by Qi et al. in 2003
21
and the
subsequent cloning of both short and long 892-amino-acid forms by Ajami
et al. in 2004.
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Due to the high structural homology of both DP8/9 with DP4
and FAP, investigations into their biochemical functions have rapidly increased
since their discovery. At present, studies have led to the implication of both
DP8/9 in immune functions, but clear physiological roles are yet to be defined
for either of the enzymes. DP8 and DP9 are closely related molecules sharing
61% amino acid identity, intracellular localization, and ubiquitous tissue
expression. Intuitively, it seems likely that DP8/9 play essential roles in human
biology, and an overlap or redundancy in function may exist between the two.
That said, it is also likely that each may have unique and independent functions
that are yet to be revealed. An inherent problem that arises when investigating
DP8 and DP9 is differentiating between the observed effects of these two
enzymes using current research tools. Until knockout animals are generated
and/or crystal structures resolved to enable the design of DP8 and DP9 selec-
tive inhibitors, this will continue to be an issue. If DP8 and DP9 are essential
intracellular enzymes with redundant functions, it will be highly beneficial for a
double DP8/9 knockout to be generated for an assessment of its viability.
Likewise, if redundant/compensatory mechanisms exist between DP8 and DP9,
then individual knockout animals should presumably result in viable offspring.
At present, only speculations can be made.
